Mitochondrial-to-nuclear translocation of apoptosis-inducing factor in cardiac myocytes during oxidant stress: potential role of poly(ADP-ribose) polymerase-1

2004 ◽  
Author(s):  
M CHEN
Keyword(s):  
Cardiac Myocytes ◽  
Potential Role ◽  
Nuclear Translocation ◽  
Oxidant Stress ◽  
Apoptosis Inducing Factor

scholarly journals EGFR-ERK induced activation of GRHL1 promotes cell cycle progression by up-regulating cell cycle related genes in lung cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Yiming He ◽  
Mingxi Gan ◽  
Yanan Wang ◽  
Tong Huang ◽  
Jianbin Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Potential Role ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Phosphorylation Site ◽  
Promoter Regions ◽  
Cycle Progression

AbstractGrainyhead-like 1 (GRHL1) is a transcription factor involved in embryonic development. However, little is known about the biological functions of GRHL1 in cancer. In this study, we found that GRHL1 was upregulated in non-small cell lung cancer (NSCLC) and correlated with poor survival of patients. GRHL1 overexpression promoted the proliferation of NSCLC cells and knocking down GRHL1 inhibited the proliferation. RNA sequencing showed that a series of cell cycle-related genes were altered when knocking down GRHL1. We further demonstrated that GRHL1 could regulate the expression of cell cycle-related genes by binding to the promoter regions and increasing the transcription of the target genes. Besides, we also found that EGF stimulation could activate GRHL1 and promoted its nuclear translocation. We identified the key phosphorylation site at Ser76 on GRHL1 that is regulated by the EGFR-ERK axis. Taken together, these findings elucidate a new function of GRHL1 on regulating the cell cycle progression and point out the potential role of GRHL1 as a drug target in NSCLC.

scholarly journals Caspase-Independent Pathway is Related to Nilotinib Cytotoxicity in Cultured Cardiomyocytes

2017 ◽  
Vol 42 (6) ◽  
pp. 2182-2193 ◽  
Author(s):  
Qinghui Yang ◽  
Chunhui Zhang ◽  
Hong Wei ◽  
Zenghui Meng ◽  
Guangnan Li ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Nuclear Translocation ◽  
Morphological Changes ◽  
H9c2 Cells ◽  
Mitochondrial Signaling ◽  
Leukemia Treatment ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor ◽  
Cultured Cardiomyocytes

Background/Aims: Cardiotoxicity is a predominant side-effect of nilotinib during chronic myeloid leukemia treatment. The underlying molecular mechanism remains unclear. The role of autophagy and mitochondrial signaling was investigated in nilotinib-treated cardiac H9C2 cells. Methods: Cytotoxicity was assessed using Cell Death Detection kit. Immunoblot and immunofluorescence staining was performed, and cathepsin B and caspase3 activity was assessed in nilotinib-treated H9C2 cells with or without distinct pathway inhibitor or specific siRNA. Results: Nilotinib time- and dose-dependently induced H9C2 apoptosis, which was not completely prevented by the pan caspase inhibitor z-VAD-fmk. Following nilotinib treatment, mitochondrial membrane potential decreased significantly accompanied with remarkable morphological changes. Nuclear translocation of mitochondrial apoptosis inducing factor (AIF) and increased p53 was detected in nilotinib-treated cells. AIF knockdown prevented nilotinib-induced increase of p53 and apoptosis. Additionally, increased cathepsin B activity was detected, and inhibition of cathepsin B by CA-074Me prevented nilotinib-induced apoptosis and nuclear translocation of AIF. Moreover, increased Atg5 and transition of LC3-I to LC3-II was revealed following nilotinib treatment. Increased cathepsin B activity and apoptosis by nilotinib was significantly prohibited by specific autophagy inhibitor bafilomycin A and Atg5 knockdown. Conclusion: Our findings demonstrate that nilotinib increases autophagy and cathepsin B activity, leading to mitochondrial AIF release and nuclear translocation, which is responsible for p53 and apoptosis induction in H9C2 cells.

Abstract 1516: Role of Oxidative Stress in Atrial Tachycardia Remodelling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Xiao-Yan Qi ◽  
Louis R Villeneuve ◽  
Balazs Ordog ◽  
Denis Chartier ◽  
David R Van Wagoner ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Atrial Tachycardia ◽  
Potential Role ◽  
Oxidant Stress ◽  
Cell Voltage ◽  
Radical Generation ◽  
X 24 ◽  
Camkii Activation

Atrial tachycardia remodeling (ATR) promotes atrial fibrillation (AF). Oxidant stress (OxS) occurs in atria of AF patients and antioxidants may be beneficial in AF. This study used a previously validated in vitro paced canine cardiomyocyte model to assess the potential role of OxS in ATR. Cultured canine atrial cardiomyocytes were paced at 1 or 3 Hz (P1, P3) for 24 hrs. I CaL was recorded with whole cell voltage clamp. Single cell superoxide production was assessed by dihydroethidium fluorescence (DHEF) imaging. ATR (3 Hz pacing x 24 hrs) decreased I CaL (Fig. A ) and induced OxS (Fig. B ). Short term induction of OxS (H 2 O 2 100 μM x 10 mins) increased I CaL (Fig. C ) and enhanced Ca 2+ loading (Indo-1 AM). 24-Hr H 2 O 2 100 μ M increased DHEF in P1 cells by 250%* (*P<0.05) and mimicked ATR, decreasing I CaL by 51%* (Fig. C ). H 2 O 2 -mediated DHEF changes were suppressed by inhibiting calmodulin (W7) or CaMKII (KN93). H 2 O 2 -induced I CaL suppression at 1 Hz was prevented by: decreasing Ca 2+ i loading by I CaL blockade (nimodipine) or Ca 2+ chelation (BAPTA-AM); W7 or KN93; antioxidants (2-MPG or N-acetylcysteine, NAC); or suppression of free radical generation via NADPH-oxidase (apocynin). 2-MPG, NAC, and apocynin prevented I CaL downregulation by 3-Hz pacing and W7, KN93 and apocynin abolished ATR-induced DHEF increases. H 2 O 2 mimics ATR by causing Ca 2+ i loading and CaMKII activation coupled to NADPH-oxidase stimulation. ATR-induced I CaL -downregulation is mediated in part by OxS generation. These findings provide insights into the pathways by which OxS contributes to ATR and present a mechanistic framework for understanding the effects of antioxidant interventions in AF.

Nuclear compartmentalization of FAK and FRNK in cardiac myocytes

2006 ◽  
Vol 290 (6) ◽  
pp. H2509-H2515 ◽  
Author(s):  
Xian Ping Yi ◽  
Jibin Zhou ◽  
Lu Huber ◽  
Jiaxiang Qu ◽  
Xuejun Wang ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Nuclear Translocation ◽  
Nuclear Bodies ◽  
Serine Phosphorylation ◽  
Double Labeling ◽  
Bright Spots ◽  
Homologous Site ◽  
Equivalent Site ◽  
Pkc Activation

Focal adhesion kinase (FAK) and FAK-related non-kinase (FRNK) accumulate in the nucleus of cardiac myocytes during hypertensive hypertrophy. Nuclear FAK and FRNK are phosphorylated on different serines and form distinct bright spots. The subnuclear distribution of serine-phosphorylated FAK and FRNK was examined in this study by double labeling with fibrillarin, a component of nucleoli, and Sam68, a constituent of Sam68 nuclear bodies. We also investigated the role of protein kinase C (PKC)-mediated phosphorylation of FAK and FRNK on nuclear translocation. PKC activation by 12- O-tetradecanoylphorbol 13-acetate treatment increased serine phosphorylation of FAK and FRNK. Specifically, FAK was phosphorylated on serine 722 but not serine 910. On the other hand, FRNK was phosphorylated on serine 217, the equivalent site of FAK serine 910, but not serine 30, the homologous site of FAK serine 722. Serine-phosphorylated FAK and FRNK redistributed into the nucleus and formed distinct patterns. FAK with phosphorylation on serine 722 colocalized with Sam68 but not fibrillarin. On the contrary, FRNK phosphorylated on 217 coexisted with fibrillarin but not Sam68. Immunoprecipitation also confirmed that FAK associated with Sam68 and FRNK interacted with fibrillarin, respectively. These results suggest that FAK and FRNK target different nuclear subdomains by their association with distinct nuclear proteins.

Abstract 862: Ser517:-phosphorylation Of Sirt1 Is Required For Its Pi3k/akt-mediated Nuclear Translocation And Cardiomyocyte Protection Against Oxidant Stress In Failing Hearts.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Masaya Tanno ◽  
Tetsuji Miura ◽  
Takayuki Miki ◽  
Toshiyuki Yano ◽  
Yoshiyuki Horio ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Oxidant Stress ◽  
C2c12 Cells ◽  
Neonatal Rat ◽  
Rat Cardiomyocytes ◽  
Intracellular Location ◽  
Transfected Cells ◽  
Induced Apoptosis

[Purpose] We recently found that SIRT1, a protein deacetylase, shuttles between the nucleus and cytoplasm. In this study, we examined the role of nuclear SIRT1 in cardiomyocyte protection against oxidant stress and involvement of PI3K/Akt in the nuclear translocation. [Methods and Results] First, the critical intracellular location of SIRT1 for its anti-apoptotic function was examined. C2C12 cells were transfected with wild-type SIRT1 (WT) or SIRT1 with site-directed mutations in the nuclear localizing signal (mtNLS) and exposed to antimycin A (AA), an oxidative stressor. AA-induced apoptosis was suppressed in WT-transfected cells expressing SIRT1 in the nuclei compared with that in mtNLS-transfected cells expressing SIRT1 in the cytoplasm (TUNEL-positive cells = 4.4±0.7% vs. 34.6±8.0%). AA-induced apoptosis and also angiotensin II-(angII)-induced apoptosis in neonatal rat cardiomyocytes (NRCM) were suppressed by resveratrol, a SIRT1 activator. This protective effect of resveratrol was attenuated by transfection of SIRT1-siRNA but not by transfection of control siRNA. Next, we assessed the role of PI3K/Akt in nuclear translocation of SIRT1. SIRT1 in NRCM was localized in both the nucleus and cytoplasm under baseline conditions, and IGF-1 induced its nuclear translocation. This effect of IGF-1 was suppressed by LY294002 (LY), a PI3K inhibitor. Deletion mutagenesis study showed that LY-induced nuclear exclusion was observed for SIRT1[223–540] but not for SIRT1[223– 489]. Replacement of serine517 with alanine (S517A) increased cytoplasmic SIRT1, and S517A showed attenuated nuclear translocation in response to IGF-1, indicating that serine517 is the target site of PI3K/Akt. Finally, to confirm heart failure-associated SIRT1 translocation in vivo, myocardial infarction was induced in WKY rats. The number of ventricular cardiomyocytes with nuclear SIRT1 at 4 weeks after infarction was significantly larger than that in sham-operated hearts (10.2±2.9% vs. 0.7±0.2%). [Conclusion] The results suggest that phosphorylation of SIRT1 at Ser517 by PI3K/Akt is involved in nuclear translocation of SIRT1, which contributes to cardiomyocyte protection from oxidant stress-mediated injury in failing hearts.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

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